Phase II clinical trial of neoadjuvant anti-PD-1 (toripalimab) combined with axitinib in resectable mucosal melanoma.

BACKGROUND: The outcome of patients with resectable mucosal melanoma is poor. Toripalimab combined with axitinib has shown impressive results in metastatic mucosal melanoma with an objective response rate of 48.3% and a median progression-free survival of 7.5 months in a phase Ib trial. It was hypothesized that this combination administered in the neoadjuvant setting might induce a pathologic response in resectable mucosal melanoma, so we conducted this trial. PATIENTS AND METHODS: This single-arm phase II trial enrolled patients with resectable mucosal melanoma. Patients received toripalimab 3 mg/kg once every 2 weeks (Q2W) plus axitinib 5 mg two times a day (b.i.d.) for 8 weeks as neoadjuvant therapy, then surgery and adjuvant toripalimab 3 mg/kg Q2W starting 2 ± 1weeks after surgery for 44 weeks. The primary endpoint was the pathologic response rate according to the International Neoadjuvant Melanoma Consortium recommendations. RESULTS: Between August 2019 and October 2021, 29 patients were enrolled and received treatment, of whom 24 underwent resection. The median follow-up time was 34.2 months (95% confidence interval 20.4-48.0 months). The pathologic response rate was 33.3% (8/24; 4 pathological complete responses and 4 pathological partial responses). The median event-free survival for all patients was 11.1 months (95% confidence interval 5.3-16.9 months). The median overall survival was not reached. Neoadjuvant therapy was tolerable with 8 (27.5%) grade 3-4 treatment-related adverse events and no treatment-related deaths. Tissue samples of 17 patients at baseline and after surgery were collected (5 responders and 12 nonresponders). Multiplex immunohistochemistry demonstrated a significant increase in CD3+ (P = 0.0032) and CD3+CD8+ (P = 0.0038) tumor-infiltrating lymphocytes after neoadjuvant therapy, particularly in pathological responders. CONCLUSIONS: Neoadjuvant toripalimab combined with axitinib in resectable mucosal melanoma demonstrated a promising pathologic response rate with significantly increased infiltrating CD3+ and CD3+CD8+ T cells after therapy.

[Efficacy analysis of hepatic arterial infusion chemotherapy combined with targeted and immune therapy followed by 125I seeds implantation in the treatment of hepatocellular carcinoma with portal vain tumor thrombus].

Objective: To investigate the safety and efficacy of Hepatic Arterial Infusion Chemotherapy(HAIC) combined with targeted and immune therapy followed by 125I seeds implantation in portal vain tumor thrombus (PVTT) in the treatment of hepatocellular carcinoma(HCC) with PVTT. Methods: A retrospective study was performed on the clinical data of 21 patients [ (11 men, 10 women) aged 34-73 (52.6±13.7) years] with HCC with PVTT in The First Affiliated Hospital of Zhengzhou University from October 2020 to October 2022, all of them were treated with HAIC plus targeted and immune therapy,and 125I seeds implanted into PVTT. The patients were followed up to January 2023, the efficacy was evaluated according to the modified version of the solid tumor efficacy evaluation criteria (mRECIST). The progression-free survival (PFS) rate, overall survival(OS) rate and portal tumor thrombus control rate at 3, 6, 12 and 18 months after treatment were recorded, and PFS and OS time were followed up. The changes of liver function, AFP, coagulation function and adverse events were observed. Results: Each patient received 2 to 7 (mean: 3.3±1.2) cycles of HAIC. 10-37 seeds (mean:16.6±6.7) were implanted per patients. The median follow-up time was 15 (range from 5 to 25) months.During the follow-up time, 15 patients showed progression and 6 patients died, and the PFS rates at 3, 6, 12, and 18 months after treatment were 90.5%, 71.4%, 42.9%, and 23.8%, respectively, and at 3, 6, 12, and 18-month OS rates were 100%, 100%, 81.0%, and 61.9%, respectively.The PVTT control rates at 3, 6, and 12 months were 90.5%, 90.5%, and 62.5%, respectively. Overall efficacy evaluation of CR rate 0, PR rate 47.6% (10/21), SD rate 38.1% (8/21), and PD rate 14.3% (3/21). The total incidence of treatment-related adverse events was 100%.Grade 3 treatment related adverse events were observed for 4 cases, the rest wereⅠtoⅡadverse events. Right upper abdominal pain, fever and hemorrhage in liver capsule related to the procedures were observed in 11(52.4%), 5(23.8%) and 3(14.3) patients, respectively. Conclusion: HAIC combined with targeted and immune therapy followed by 125I seeds implantation in PVTT is a safe and efficacy therapy for HCC with PVTT.

[Analysis of the safety, accuracy, and factors influencing bleeding complications in CT-guided puncture biopsy of brain occupying lesions].

Objective: To investigate the safety and accuracy of CT-guided intracranial puncture biopsy and the possible influencing factors of postoperative bleeding complications. Methods: A case series study. A retrospective analysis was conducted on 101 patients who underwent CT-guided intracranial puncture biopsy at the First Affiliated Hospital of Zhengzhou University from January 2017 to December 2021. The basic data of patients and the safety and accuracy of CT-guided intracranial puncture biopsy were analyzed statistically. Univariate and multivariate logistic regression analysis were used to screen the influencing factors of bleeding complications in CT-guided intracranial puncture biopsy, and the bleeding complications in glioma subgroup were analyzed. Results: Among the 101 patients, 53 were males and 48 were females, aged (53.7±17.2) years. The average diameter of intracranial lesions was (3.5±1.4) cm, while the vertical distance from the lesion to the meninges was (2.4±1.7) cm. The needle's intracranial depth reached (3.2±1.8) cm, with adjustments averaging (3±1) occurrences and an average procedural duration of (40.2±12.9) minutes. Pathological diagnoses included glioma (36 cases), gliosis (3 cases), lymphoma (32 cases), metastatic tumors (7 cases), inflammatory lesions (13 cases), and 10 indeterminate cases. The positive rate of puncture pathology was 90.1% (91/101), and the diagnostic coincidence rate was 94.0% (78/83). The incidence of bleeding complications in CT-guided intracranial puncture biopsy was 26.7% (27/101), of which 23 cases had small intratoma or needle path bleeding, 4 cases had massive bleeding, and 2 cases died. The patients were divided into bleeding group (n=27) and no bleeding group (n=74), according to the presence or absence of bleeding. The results of univariate logistic regression analysis showed that thrombin time≥15 s and the number of needle adjustment were the factors affecting the occurrence of bleeding complications (both P<0.05), and the results of multivariate logistic regression showed that thrombin time≥15 s was the related factor for bleeding. Patients with thrombin time≥15 s had a 3.045 times higher risk of bleeding than those with thrombin time<15 s (OR=3.045,95%CI:1.189-7.799,P=0.020). Among the 101 patients, 36 cases of midbrain glioma were divided into low-grade glioma group (n=11) and high-grade glioma group (n=25) according to the pathological grade. Subgroup analysis showed that the risk of bleeding for high-grade gliomas was 9.231 times higher than that for low-grade gliomas (OR=9.231,95%CI:1.023-83.331,P=0.031). Conclusions: CT-guided intracranial puncture biopsy is safe and feasible with high accuracy. Complication rates are associated with thrombin time≥15 s, especially high-grade glioma, which increases the risk of postoperative bleeding.

[Advances in the co-signal molecular function of Mtb-specific T lymphocytes].

Costimulatory and co-inhibitory receptors on T lymphocytes play an essential role in the immune response. There is increasing evidence that the expression of co-signal molecules on T cells is altered in infection, tumor, autoimmunity, and other diseases, and that intervention of co-signal molecules can be used in the immunotherapy. This paper reviewed the costimulatory and coinhibitory receptors on Mtb-specific T lymphocytes and further explained the mechanism of co-signal molecules in the progression of tuberculosis, to provide a reference for future research and clinical application.

[Clinical analysis of adverse reactions in patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis treated with delamanid-containing regimen].

Objective: To explore the characteristics of adverse drug reactions during the 24-week therapy with delamanid-containing regimen for patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB). Methods: The prospective multicenter study was conducted from June 2020 to June 2023. A total of 608 eligible patients with MDR/RR-PTB were enrolled in 26 tuberculosis medical institutions in China including 364 males and 79 females, aged 39.6(19.0-68.0) years. Patients were treated with chemotherapy regimens containing delamanid. Patients were closely supervised during treatment of medication, and all adverse reactions occurring during treatment were monitored and recorded. The clinical characteristics of adverse reactions were evaluated by descriptive analysis. Chi-square test and multivariate logistic regression were used to analyze the related factors of QTcF interval prolongation (QT corrected with Fridericia's formula). Results: Of the 608 patients enrolled in this study, 325 patients (53.5%) reported 710 adverse events within 24 weeks of treatment. The top 6 most common complications were hematological abnormalities (143 patients, 23.5%), QT prolongation (114 patients, 18.8%), liver toxicity (85 patients, 14.0%), gastrointestinal reaction (41 patients, 6.7%), peripheral neuropathy (25 patients, 4.1%) and mental disorders (21 patients, 3.5%). The prolongation of QT interval mostly occurred in the 12th week after the first dose of medication. Serious adverse reactions occurred in 21 patients (3.5%). There were 7 patients (1.2%) with mental disorders, including 2 patients (0.3%) with severe mental disorders. Conclusions: The safety of dalamanid-based regimen in the staged treatment of MDR/RR-PTB patients was generally good, and the incidence of adverse reactions was similar to that reported in foreign studies. This study found that the incidence of QT interval prolongation in Chinese patients was higher than that reported overseas, suggesting that the monitoring of electrocardiogram should be strengthened when using drugs containing delamanid that may cause QT interval prolongation.

[The current situation of occupational health in the Internet industry and countermeasures].

As an important force in promoting the transformation and upgrading of the national economy, the occupational health of the Internet industry's employees has received widespread attention. This paper examines the current situation of occupational health risks and management in the Internet industry at home and abroad, and on this basis reveals the physical and mental health problems of Internet industry employees. Combining the existing regulations, policies and standard documents at home and abroad, countermeasures are proposed to improve the relevant laws and regulations and their guidelines, implement relevant job design requirements, build a healthy working environment, optimise the work management system and carry out workplace health promotion, in order to provide ideas to accelerate the improvement of occupational health issues in the Internet industry.

[Advance in occupational health risks and management of shift work].

The occupational health issues of shift workers has received increasing attention in the field of occupational health, and discussed in this article through literature review on the health risks and management of shift work both domestically and internationally. Based on this, a series of impacts of shift work on the physiological and psychological health of workers, as well as their family and social life, are revealed. Combined with relatively mature regulations and policies in foreign countries, it is proposed that China should fully learn from the relevant experience of health management in shift work abroad, Strengthen research and explore effective management intervention measures to provide ideas for accelerating the development of scientifically feasible regulations and policies related to occupational health in shift work in China.

Fusarium diversity associated with diseased cereals in China, with an updated phylogenomic assessment of the genus.

Fusarium species are important cereal pathogens that cause severe production losses to major cereal crops such as maize, rice, and wheat. However, the causal agents of Fusarium diseases on cereals have not been well documented because of the difficulty in species identification and the debates surrounding generic and species concepts. In this study, we used a citizen science initiative to investigate diseased cereal crops (maize, rice, wheat) from 250 locations, covering the major cereal-growing regions in China. A total of 2 020 Fusarium strains were isolated from 315 diseased samples. Employing multi-locus phylogeny and morphological features, the above strains were identified to 43 species, including eight novel species that are described in this paper. A world checklist of cereal-associated Fusarium species is provided, with 39 and 52 new records updated for the world and China, respectively. Notably, 56 % of samples collected in this study were observed to have co-infections of more than one Fusarium species, and the detailed associations are discussed. Following Koch's postulates, 18 species were first confirmed as pathogens of maize stalk rot in this study. Furthermore, a high-confidence species tree was constructed in this study based on 1 001 homologous loci of 228 assembled genomes (40 genomes were sequenced and provided in this study), which supported the "narrow" generic concept of Fusarium (= Gibberella). This study represents one of the most comprehensive surveys of cereal Fusarium diseases to date. It significantly improves our understanding of the global diversity and distribution of cereal-associated Fusarium species, as well as largely clarifies the phylogenetic relationships within the genus. Taxonomic novelties: New species: Fusarium erosum S.L. Han, M.M. Wang & L. Cai, Fusarium fecundum S.L. Han, M.M. Wang & L. Cai, Fusarium jinanense S.L. Han, M.M. Wang & L. Cai, Fusarium mianyangense S.L. Han, M.M. Wang & L. Cai, Fusarium nothincarnatum S.L. Han, M.M. Wang & L. Cai, Fusarium planum S.L. Han, M.M. Wang & L. Cai, Fusarium sanyaense S.L. Han, M.M. Wang & L. Cai, Fusarium weifangense S.L. Han, M.M. Wang & L. Cai. Citation: Han SL, Wang MM, Ma ZY, Raza M, Zhao P, Liang JM, Gao M, Li YJ, Wang JW, Hu DM, Cai L (2023). Fusarium diversity associated with diseased cereals in China, with an updated phylogenomic assessment of the genus. Studies in Mycology 104: 87-148. doi: 10.3114/sim.2022.104.02.

[The effect of lncRNA ADPGK-AS1 on the proliferation and apoptosis of retinoblastoma cells by targeting miR-200b-5p].

Objective: To explore the effect of lncRNA ADPGK-AS1 on the proliferation and apoptosis of retinoblastoma cells and its possible mechanism. Methods: The tumor tissues of 31 patients with retinoblastoma admitted to Henan Provincial Eye Hospital from February to June 2020 and their corresponding normal tissues adjacent to the cancer were collected. The expression levels of lncRNA ADPGK-AS1 and miR-200b-5p in retinoblastoma tissues and normal adjacent tissues were detected by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR). Human retinal epithelial cell ARPE-19, human retinoblastoma cell Y-79 and WERI-Rb-1 were cultured in vitro. The expression levels of lncRNA ADPGK-AS1 and miR-200b-5p were detected by qRT-PCR. Y-79 cells were randomly divided into si-con group, si-lncRNA ADPGK-AS1 group, miR con group, miR-200b-5p group, si-lncRNA ADPGK-AS1+ anti-miR con group, and si-lncRNA ADPGK-AS1+ anti-miR-200b-5p group. The proliferation, cloning and apoptosis of cells in each group were detected by tetramethylazol blue method, plate cloning test and flow cytometry, respectively. The targeting relationship between lncRNA ADPGK-AS1 and miR-200b-5p was detected by double luciferase report test, and the expression level of cleaved-caspase-3 protein was detected by western blot. Results: Compared with the adjacent tissues, the expression of lncRNA ADPGK-AS1 in retinoblastoma tissues was increased (P<0.05), while the expression of miR-200b-5p was decreased (P<0.05). Compared with ARPE-19 cells, the expression of lncRNA ADPGK-AS1 in Y-79 and WERI-Rb-1 cells was increased (P<0.05), while the expression of miR-200b-5p was decreased (P<0.05). Compared with the si-con group, the cell viability of the si-lncRNA ADPGK-AS1 group was reduced (1.06±0.09 vs 0.53±0.05, P<0.05), the number of cell clone formation was reduced (114.00±8.03 vs 57.00±4.13, P<0.05), while the apoptosis rate [(7.93±0.68)% vs (25.43±1.94)%] and the protein level of cleaved-caspase-3 were increased (P<0.05). Compared with the miR-con group, the cell viability of the miR-200b-5p group was decreased (1.05±0.08 vs 0.57±0.05, P<0.05), the number of cell clone formation was decreased (118.00±10.02 vs 64.00±5.13, P<0.05), while the apoptosis rate [(7.89±0.71)% vs (23.15±1.62)%] and the protein level of cleaved-caspase-3 were increased (P<0.05). lncRNA ADPGK-AS1 could target the expression of miR-200b-5p. Compared with the si-lncRNA ADPGK-AS1+ anti-miR-con group, cell viability of the si-lncRNA ADPGK-AS1+ anti-miR-200b-5p group was increased (0.53±0.04 vs 1.25±0.10, P<0.05), and the number of cell clones was increased (54.00±4.39 vs 125.00±10.03, P<0.05), while the rate of apoptosis [(25.38±1.53)% vs (9.76±0.71)%] and the protein level of cleaved-caspase-3 were decreased (P<0.05). Conclusion: Interfering with the expression of lncRNA ADPGK-AS1 could inhibit the proliferation and clone formation and induce apoptosis of retinoblastoma cells by targeting the expression of miR-200b-5p.

[Analysis of the safety and diagnostic efficiency of CT-guided percutaneous biopsy of pancreatic space-occupying lesions using large needle:comparison of trans-organ biopsy approach and non-trans-organ biopsy approach].

Objective: To compare the safety and diagnostic efficiency of CT-guided trans-organ and non-trans-organ large needle biopsy in the diagnosis of pancreatic space-occupying lesions. Methods: The clinical data of 367 patients with pancreatic mass who underwent CT-guided percutaneous biopsy in the First Affiliated Hospital of Zhengzhou University from January 2019 to January 2022 were retrospectively analyzed, including 211 males and 156 females, aged 18 to 87 (60.7±11.8) years old. They were divided into a trans-organ route group (n=142) and a non-trans-organ route group (n=225) according to whether traversing the organs during the procedures. The imaging data, pathological results, puncture process and complications of patients of the two groups were recorded. The successful rate for obtaining tissue,one-time successful diagnosis rate, accuracy, sensitivity, specificity, false negative rate and the incidence of complications were compared between the two groups. Results: There was no significant difference in baseline data between the two groups (all P>0.05).There were 28, 57, 24, and 33 biopsies were performed via a pathway traversing liver, stomach, small bowel and colon, respectively. The overall sampling success rates of the two groups were 100%.The one-time successful diagnosis rate did not show statistically difference between the two groups [86.6%(123/142) vs 87.1%(196/225),P=0.892]. There was no statistically difference in accuracy, sensitivity and false negative rates between trans-organ route group and non-trans-organ routegroup [92.3%(131/142) vs 92.0%(207/225), 91.8% (123/134) vs 90.0%(190/211) and 8.2% (11/134) vs 10.0%(21/211), all P>0.05]. The specificity was 100% in both groups. The common complications of the two groups were increased pancreatic amylase and hematoma, and there was no significant difference in the incidence of complications between the trans-organ route group and the non-trans-organ route group [10.6% (15/142) vs 12.4% (28/225), P=0.585]. In the trans-organ route group, 5 patients had increased pancreatic amylase and 10 patients had local hematoma, all of which were improved after conservative treatment. In the non-organ route group, 11 patients had elevated pancreatic amylase, and 17 patients had local hematoma, 1 case received surgical treatment due to bleeding, the rest were improved by conservative treatment. Conclusion: CT-guided percutaneous transabdominal organ large needle biopsy of pancreatic space-occupying lesions has the comparable diagnostic efficiency and safety as non-transabdominal organ approach.

[Periodic dynamic observation and analysis of cellular and humoral immunity indexes of adults infected with Omicron BA.1].

Objective: To analyze the immunological characteristics and antibody changes of patients infected with the Omicron BA.1 and evaluate the possibility of secondary infection. Methods: A total of 104 patients infected with Omicron BA.1 in the Jinnan District of Tianjin from January 8 to February 2, 2022, were included in the study. The control group and case group were matched 1∶1 based on age, sex and vaccination status. Serum was collected from the case group and control group at 3, 6 and 9 months after infection. The serum levels of interleukin4 (IL-4), IL-5 and interferon-gamma (IFN-γ), as well as the positive rates of IgG, IgG1 and IgG2, were detected by ELISA. Results: The highest concentration of IFN-γ in the case group at 6 months after infection was 145.4 pg/ml, followed by a decrease in concentration. The concentrations of IL-4 and IL-5 began to decrease at 6 months after infection (all P<0.001). There was no significant difference in the IgG2 positive rate between the case group and the control group at 6 months after BA.1 infection. However, at 9 months, there was a significant decrease compared to the control group (P=0.003). The ratio of IFN-γ/IL4 at 3 months after infection in the case group was lower than that in the control group (P<0.001). There was no significant difference in the ratio between the case group and the control group at 9 months after infection. Conclusion: The cellular immune function has been impaired at 3 months after infection with BA.1, and the specific cellular immune and humoral immune functions decrease significantly after 6 months, and the risk of secondary infection increases.

[The value of cell free DNA of Mycobacterium tuberculosis in the early diagnosis of tuberculous meningitis].

Objective: To detect the cell-free DNA of Mycobacterium tuberculosis (Cf-TB) in the cerebrospinal fluid (CSF) of patients with tuberculous meningitis (TBM), and to assess the diagnostic value of this method for TBM. Methods: We prospectively included patients with suspected meningitis from the Department of Tuberculosis, Beijing Chest Hospital, Department of Neurology, Beijing Chaoyang Hospital and Department of Neurology, 263 Hospital of the People's Liberation Army from September 2019 to March 2022. A total of 189 patients were included in this study. Among them, 116 were male and 73 were female, aged from 7 to 85 years, with an average of (38.5±19.1) years. The CSF specimens of the patients were collected for Cf-TB, MTB culture and Xpert MTB/RIF. SPSS 20.0 was used for statistical analysis and the difference was statistically significant with P<0.05. Results: Among the 189 patients, there were 127 patients in the TBM group and 62 patients in the non-TBM group. The sensitivity of Cf-TB was 50.4% (95%CI 41.4%-59.3%), the specificity was 100% (95%CI 92.7%-100.0%), the positive predictive value was 100% (95%CI 92.9%-100.0%), and the negative predictive value was 49.6% (95%CI 40.6%-58.6%). Using clinical diagnosis as the gold standard, the sensitivity of Cf-TB was 50.4% (64/127), which was significantly higher than that of MTB culture (8.7%, 11/127) and Xpert MTB/RIF (15.7%,20/127) (all P<0.001). Using etiology as the gold standard, the sensitivity of Cf-TB was 72.7% (24/33), which was significantly higher than that of MTB culture [33.3%, 11/33, (χ2=10.28, P=0.001)] and was similar to Xpert MTB/RIF (60.6%, 20/33) (χ2=1.091, P=0.296). Conclusion: The sensitivity of the Cf-TB test was significantly higher than that of CSF MTB culture and Xpert MTB/RIF. Cf-TB may provide evidence for earlier diagnosis and treatment of TBM.

[Predictive value of the proportion of hibernating myocardium in total perfusion defect on reverse remodeling in patients with HFrEF underwent coronary artery bypass graft].

Objective: To evaluate the predictive value of the proportion of hibernating myocardium (HM) in total perfusion defect (TPD) on reverse left ventricle remodeling (RR) after coronary artery bypass graft (CABG) in patients with heart failure with reduced ejection fraction (HFrEF) by 99mTc-methoxyisobutylisonitrile (MIBI) single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) combined with 18F-flurodeoxyglucose (FDG) gated myocardial imaging positron emission computed tomography (PET). Methods: Inpatients diagnosed with HFrEF at the Cardiac Surgery Center, Anzhen Hospital of Capital Medical University from January 2016 to January 2022 were prospectively recruited. MPI combined with 18F-FDG gated PET was performed before surgery for viability assessment and the patients received follow-up MPI and 18F-FDG gated PET at different stages (3-12 months) after surgery. Δ indicated changes (post-pre). Left ventricular end-systolic volume (ESV) reduced at least 10% was defined as RR, patients were divided into reverse remodeling (RR+) group and the non-reverse group (RR-). Binary logistic regression analysis was used to identify predictors of RR. Receiver operating characteristic (ROC) curve analysis was performed and the area under the curve (AUC) was calculated to assess the cut-off value for predicting RR. Additionally, we retrospectively enrolled inpatients with HFrEF at the Cardiac Surgery Center, Anzhen Hospital of Capital Medical University from January 2021 to January 2022 as the validation group, who underwent MPI and 18F-FDG gated PET before surgery. Echocardiography was performed before CABG and after CABG (3-12 months). In the validation group, the reliability of obtaining the cut-off value for the ROC curve was verified. Results: A total of 28 patients with HFrEF (26 males; age (56.9±8.7) years) were included in the prospective cohort. HM/TPD was significantly higher in the RR+ group than in the RR- group ((51.8%±17.9%) vs. (35.7%±13.9%), P=0.016). Binary logistic regression analysis revealed that HM/TPD was an independent predictor of RR (Odds ratio=1.073, 95% Confidence interval: 1.005-1.145, P=0.035). ROC curve analysis revealed that HM/TPD=38.3% yielded the highest sensitivity, specificity, and accuracy (all 75%) for predicting RR and the AUC was 0.786 (P=0.011). Meanwhile, a total of 100 patients with HFrEF (90 males; age (59.7±9.6) years) were included in the validation group. In the validation group, HM/TPD=38.3% predicted RR in HFrEF patients after CABG with the highest sensitivity, specificity and accuracy (82%, 60% and 73% respectively). Compared with the HFrEF patients in the HM/TPD<38.3% group (n=36), RR and cardiac function improved more significantly in the HM/TPD≥38.3% group (n=64) (all P<0.05). Conclusions: Preoperative HM/TPD ratio is an independent factor for predicting RR in patients with HFrEF after CABG, and HM/TPD≥38.3% can accurately predict RR and the improvement of cardiac function after CABG.

Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.

BACKGROUND: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

Evidence of a shared binding site for Bacillus thuringiensis Cry1Ac and Cry2Aa toxins in Cnaphalocrocis medinalis cadherin.

Insect midgut cadherins function as receptors and play critical roles as protein receptors of insecticidal Bacillus thuringiensis (Bt) toxins used as biopesticides and in Bt transgenic crops worldwide. Here, we cloned and characterized the full-length midgut cadherin (CmCad) cDNA from the rice leaffolder (Cnaphalocrocis medinalis), a destructive pest of rice in many Asian countries. Expression of recombinant proteins corresponding to the extracellular domain of CmCad allowed testing binding of Cry proteins. Results from in vitro ligand blotting and enzyme-linked immunosorbent assays supported that the extracellular domain of CmCad contains regions recognized by both Cry1Ac and Cry2Aa. Molecular modelling and docking simulations indicated that binding to both Cry1Ac and Cry2Aa is localized primarily within a CmCad motif corresponding to residues T1417-D1435. A recombinant CmCad protein produced without residues T1417-D1435 lacked binding to Cry1Ac and Cry2Aa, confirmed our modelling predictions that CmCad has a shared Cry1Ac and Cry2Aa binding site. The potential existence of a shared binding region in CmCad suggests that caution should be taken when using combinations of Cry1Ac and Cry2Aa in pyramided transgenic rice, as their combined use could speed the evolution of resistance to both toxins.

Manganese promoted wheat straw decomposition by regulating microbial communities and enzyme activities.

AIMS: This study investigated the dose-effect of manganese (Mn) addition on wheat straw (WS) decomposition, and explored the potential mechanisms of Mn involved in the acceleration of WS decomposition in regards to the soil microbial communities and enzyme activities. METHODS AND RESULTS: A 180-day incubation experiment was performed to examine the decomposition of WS under four Mn levels, that is, 0, 0.25, 1 and 2 mg g-1 . The effects of microbial communities and enzyme activities were evaluated using control (0 mg g-1 ) and Mn (0.25 mg g-1 ) treatments. Our results revealed that Mn (0.25 mg g-1 ) addition significantly increased WS decomposition, and enhanced the release of carbon and nitrogen. Optimal Mn addition (0.25 mg g-1 ) also caused significant increases in the activity of neutral xylanase (NEX), laccase (Lac), manganese peroxidase (MnP) and lignin peroxidase (LiP) within the incubation period. Mn (0.25 mg g-1 ) addition also enriched some operational taxonomic units (OTUs) that, in turn, had the potential ability to decompose crop straw, such as secreting lignocellulolytic enzymes. CONCLUSIONS: Mn (0.25 mg g-1 ) could promote WS decomposition through enrichment of the microbial species involved in biomass decomposition, which enhanced the lignocellulose-degrading enzyme activity. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides evidence for Mn to promote WS biodegradation after Mn application, opening new windows to improve the utilization efficiency of crop residues.

Investigation on knowledge level about rational use of antimicrobial drugs among pharmacists in medical institutions in Shanxi province, China.

OBJECTIVE: To investigate the pharmacist's knowledge about rational use of antimicrobials in Shanxi of China, so as to find out the problems and provide support for the management of antimicrobials. METHODS: A questionnaire survey was conducted, which included the basic information of the respondents, the basic knowledge about antimicrobial management and the related knowledge about antimicrobial drugs. SPSS 25.0 was used for statistical analysis. RESULTS: A total of 462 pharmacists were investigated. The average score of the knowledge related to rational use of antimicrobials was 10.49 ± 4.05. It showed that the hospital type, grade, pharmacist's education, professional title and years of experience had effect on the pharmacist's knowledge level about antimicrobial drugs (P < 0.05). Multivariable logistic regression analysis showed that hospital grade and pharmacist's education were the main influencing factors (P < 0.05). CONCLUSION: Pharmacists have insufficient knowledge about the rational use of antibacterial drugs. It is essential to strengthen the training in management regulations and application of antibacterial drugs.

[Risk factors of recurrence or metastasis in patients with medullary thyroid carcinoma].

Objective: To analyze the risk factors of recurrence or metastasis of medullary thyroid carcinoma (MTC) and the influencing factors of disease-free survival (DFS). Methods: The clinicopathological data of MTC patients who visited Tianjin Medical University Cancer Institute and Hospital and underwent surgery from August 2014 to August 2019 were retrospectively analyzed. The patients were divided into recurrence or metastasis group and no recurrence or metastasis group. Multivariate logistic regression analysis was used to analyze the risk factors for recurrence or metastasis. Kaplan-Meier survival analysis and Cox regression analysis were used to determine the risk factors of DFS. Results: A total of 158 MTC patients were enrolled in final analysis, including 83 females and 75 males, with a median age of 52 (19-74) years. There were 146 cases of sporadic MTC (92.4%) and 12 cases of familial MTC (7.6%), respectively. Bilateral thyroid lesions presented in 33 cases (20.9%) and multiple lesions presented in 57 cases (36.1%), respectively. The median follow-up time was 59.7 (10.0-93.0) months and the median DFS was 55.5 (0-92.9) months. Presence of multifocality, the largest tumor size>2 cm, T3/4, N1b, clinical stage Ⅲ/Ⅳ, lymph node metastasis ratio (LNR)>0.3, preoperative calcitonin>2 000 ng/L, postoperative calcitonin>40 ng/L and no biochemical cure were significantly correlated with the recurrence or metastasis and DFS of MTC (all P<0.05). Clinical stage Ⅲ/Ⅳ (OR=36.57, 95%CI: 1.33-1 006.98, P=0.033), the largest tumor size>2 cm (OR=5.81, 95%CI: 1.01-33.33, P=0.049), multifocality (OR=3.64, 95%CI: 1.03-12.88, P=0.045) and postoperative calcitonin>40 ng/L (OR=15.03, 95%CI: 1.39-162.61, P=0.026) were independent risk factors of recurrence or metastasis. Clinical stage Ⅲ/Ⅳ (HR=19.39, 95%CI:1.40-268.19, P=0.027), the largest tumor size>2 cm (HR=3.64, 95%CI: 1.02-13.02, P=0.047) and postoperative calcitonin>40 ng/L (HR=10.68, 95%CI: 1.34-84.95, P=0.025) were influencing factors for DFS (all P<0.05). Conclusion: The larger tumor size, advanced clinical stage and higher postoperative calcitonin at the initial treatment of MTC are risk factors for recurrence or metastasis and influencing factors for DFS.

[Correlation between dyslipidemia and the risk of papillary thyroid carcinoma].

Objective: To investigate the correlation between dyslipidemia and the risk of papillary thyroid carcinoma (PTC). Methods: A case-control study was conducted. PTC patients diagnosed by pathology in Tianjin Medical University Cancer Institute and Hospital from April 2014 to August 2019 were enrolled as the experimental group, and healthy controls in the physical examination center at the same time were also enrolled as the control group. The demographic data and blood lipid parameters of the subjects were collected. Multivariate logistic analyses were used to assess the correlation between dyslipidemia and the risk of PTC. Results: A total of 2 000 cases of PTC were enrolled, with a mean age of (42±12) years, including 1 419 females (71.0%) and 581 males (29.0%). There were 4 524 cases in the control group, with a mean age of (42±9) years, including 3 311 females (73.2%) and 1 213 males (26.8%). There was no statistically difference in age and gender between the two groups (both P>0.05). Compared with the control group, triglyceride (TG) [(1.7±1.1) vs (1.4±1.0) mmol/L, P<0.001] and low-density lipoprotein (LDL) [(2.9±0.8) vs (2.8±0.7) mmol/L, P=0.015] increased in peripheral blood of PTC patients, while high-density lipoprotein (HDL) [(1.3±0.4) vs (1.4±0.3) mmol/L, P<0.001] decreased, but the difference was not statistically significant in total cholesterol (TC) [(4.9±1.0) vs (4.9±0.8) mmol/L, P=0.172]. After adjusting for age and gender, increase of TC (OR=1.20, 95%CI: 1.06-1.34, P=0.003), TG (OR=1.73, 95%CI: 1.55-1.94, P<0.001), LDL (OR=1.21, 95%CI: 1.08-1.36, P=0.001), LDL/HDL (OR=1.77, 95%CI: 1.56-2.02, P<0.001) and decrease of HDL (OR=3.15, 95%CI: 2.78-3.58, P<0.001) were the related factors of PTC. Conclusions: Compared with the control group, patients with PTC have higher level of TG and LDL and lower level of HDL. Dyslipidemia is an important factor related to the risk of PTC.

[Role of Dipeptidyl peptidase inhibitors in lung ischemia-reperfusion injury].

Lung ischemia-reperfusion injury (LIRI)is a common complication after lung transplantation and cardiopulmonary bypass. It is an important factor affecting the success rate of transplantation. Its specific pathogenesis has not yet been fully elucidated. It is very significant to find the targets and drugs for the prevention and treatment of LIRI in order to improving the utilization rate of "marginal donor lung" and the long-term survival rate of lung transplant patients. Dipeptidyl peptidase 4(DPP4) inhibitors are a class of oral hypoglycemic agents. Previous studies have shown that DPP4 inhibitors have a variety of pharmacological activities, including anti-inflammatory, anti-fibrotic, immunomodulatory and other extrapancreatic functions. Recent studies have shown that DPP4 inhibitors may alleviate LIRI through various mechanisms, including inhibiting inflammatory responses, reducing oxidative stress, regulating blood glucose levels, and activating autophagy. This article reviewed the clinical and preclinical applications and mechanisms of DPP4 inhibitors in LIRI.